rs745480657

Variant names:

• chr17-8115607-C-T
• rs745480657
• NM_021628.3:c.434G>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS3 PP3 PP5_Very_Strong

The NM_021628.3(ALOXE3):​c.434G>A​(p.Arg145His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,612,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002238144: Studies have shown that this missense change results in skipping of exon 4 and introduces a premature termination codon (PMID:19131948)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: ALOXE3 NM_021628.3 missense, splice_region
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.70
• Publications: 4 publications found

Genes affected

ALOXE3 (HGNC:13743): (arachidonate lipoxygenase 3) This gene is a member of the lipoxygenase family, which are catabolized by arachidonic acid-derived compounds. The encoded enzyme is a hydroperoxide isomerase that synthesizes a unique type of epoxy alcohol (8R-hydroxy-11R,12R-epoxyeicosa-5Z,9E,14Z-trienoic acid) from 12R-hydroperoxyeicosatetraenoic acid (12R-HPETE). This epoxy alcohol can activate the the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha), which is implicated in epidermal differentiation. Loss of function of the enzyme encoded by this gene results in ichthyosis, implicating the function of this gene in the differentiation of human skin. This gene is part of a cluster of lipoxygenase genes on 17p13.1. Mutations in this gene result in nonbullous congenital ichthyosiform erythroderma (NCIE). Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Sep 2009]

ALOXE3 Gene-Disease associations (from GenCC):

• autosomal recessive congenital ichthyosis 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• congenital non-bullous ichthyosiform erythroderma

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• lamellar ichthyosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• self-healing collodion baby

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002238144: Studies have shown that this missense change results in skipping of exon 4 and introduces a premature termination codon (PMID: 19131948).; SCV003918489: "in vitro functional analysis in a mini gene assay showed that p.(Arg145His) leads to skipping of the following exon and a frameshift, denoted as p.Arg119GlyfsX12 (Eckl et al., 2009)"
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-8115607-C-T is Pathogenic according to our data. Variant chr17-8115607-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 39550.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021628.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALOXE3	NM_021628.3	MANE Select	c.434G>A	p.Arg145His	missense splice_region	Exon 4 of 16	NP_067641.2	Q9BYJ1-1
	ALOXE3	NM_001165960.1		c.830G>A	p.Arg277His	missense splice_region	Exon 4 of 16	NP_001159432.1	Q9BYJ1-2
	ALOXE3	NM_001369446.1		c.434G>A	p.Arg145His	missense splice_region	Exon 3 of 15	NP_001356375.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALOXE3	ENST00000448843.7	TSL:1 MANE Select	c.434G>A	p.Arg145His	missense splice_region	Exon 4 of 16	ENSP00000400581.2	Q9BYJ1-1
	ALOXE3	ENST00000380149.6	TSL:1	c.434G>A	p.Arg145His	missense splice_region	Exon 3 of 15	ENSP00000369494.2	Q9BYJ1-1
	ALOXE3	ENST00000318227.4	TSL:2	c.434G>A	p.Arg145His	missense splice_region	Exon 4 of 16	ENSP00000314879.4	Q9BYJ1-1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000318 AC: 8 AN: 251466 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1459852 Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16 AN XY: 726384

African (AFR) AF: 0.0000299 AC: 1 AN: 33420

American (AMR) AF: 0.0000447 AC: 2 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000991 AC: 11 AN: 1110158

Other (OTH) AF: 0.00 AC: 0 AN: 60336

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74446

African (AFR) AF: 0.00 AC: 0 AN: 41524

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Autosomal recessive congenital ichthyosis 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	0.054
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.72	T
M_CAP	Uncertain	0.099	D
MetaRNN	Benign	0.38	T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.7
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.40
Sift	Benign	0.092	T
Sift4G	Benign	0.26	T
Polyphen		0.12	B
Vest4		0.42
MutPred		0.61		Loss of MoRF binding (P = 0.016)
MVP		0.90
MPC		0.96
ClinPred		0.35	T
GERP RS		4.5
Varity_R		0.074
gMVP		0.27
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.77		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.77		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs745480657; hg19: chr17-8018925;